We are investigating how heparan sulfate influences FGFR2b signaling in specific progenitor cell types in the epithelium. A controversy remains in the HS field as to whether HS function requires specific patterns of sulfation or simply charge density. The reported function of 3-O-sulfated HS is to bind to antithrombin and the herpes simplex virus glycoprotein, gD1. We analyzed the expression of sulfotransferase enzymes in the SMG. We found that Hs3st-modified HS was present on the SMG epithelium and that RNAi knockdown of Hs3st reduces morphogenesis and proliferation. We are investigating how FGFR2b signaling controls HS production on the cell surface of epithelial end bud progenitor cells. We are also identifying the signals that initiate the innervation of the salivary gland. Nerves often follow alongside blood vessels to navigate to their targets using similar sets of guidance cues. However, defining the signals that initiate the association between the peripheral nervous system and the salivary epithelium will be important to regenerate or engineer functioning organs. During submandibular gland (SMG) organogenesis innervation begins when neural crest-derived neurons condense around the epithelial duct to form ganglia, which subsequently extend axons to innervate the epithelium of the gland. We are studying epithelial-derived factors that initiate the neuronal-epithelial communication resulting in neurons condensing around the duct. These epithelial signals are dependent on the localized repression of FGF signaling within the duct. In contrast, enhanced epithelial FGF signaling antagonizes these factors, resulting in defects in epithelial-neuronal communication leading to disrupted ganglia formation and epithelial morphology. This also results in a subsequent depletion of the epithelial progenitor cell reservoir. Our studies demonstrate that epithelial-derived factors are required for gangliogenesis and association with the epithelial duct. Signals that promote gangliogenesis and neuronal-epithelial interactions may inform organ engineering, regeneration, and repair.